SYNTHESIS, DNA-BINDING, TOPOISOMERASE-II INHIBITION AND CYTOTOXICITY OF 2 GUANIDINE-CONTAINING ANTHRACENE-9,10-DIONES

Two anthraquinone derivatives of the anticancer drugs mitoxantrone and ametantrone were examined for their ability to bind to DNA and to mod ulate the formation of topoisomerase-DNA cleavable complexes in vitro. The guanidinium groups introduced at the termini of the two aminoethy lamino side chains of mitoxantrone can reinforce the interaction with DNA as judged from thermal denaturation studies with calf thymus DNA a nd polynucleotides. Footprinting experiments indicate that the binding to DNA of compound SR107 lacking the 5,8-hydroxyl substituents is ess entially nonspecific whereas its congener SR103 interacts preferential ly with GC-rich sequences, particularly those containing 5'-(A/T)CG si tes. Compound SR103, which bears two hydroxyl groups on the anthraquin one chromophore, promotes the cleavage of DNA by topoisomerase II and is cytotoxic toward human KB carcinoma cells in vitro. In contrast, th e analogue SR107, which lacks OH groups, has no effect on topoisomeras e II and is not cytotoxic.